Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. To date, there is still no effective antihypercholesterolemic agent commercially available that has found wide patient acceptance. The bile acid sequestrants seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
There are agents known, however, that are very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. These agents include the natural fermentation products compactin and mevinolin and a variety of semisynthetic and totally synthetic analogs thereof.
The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR2## wherein X is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino or acetylamino;
R' is ##STR3## wherein Q is R.sup.3 ##STR4## R.sup.3 is hydrogen or hydroxy; R.sup.2 is hydrogen or methyl; and PA1 a, b, c and d are single bonds, one of a, b, c and d is a double bond or a and c or b and d are double bonds provided that when a is a double bond, Q is ##STR5## PA1 R.sup.4 and R.sup.5 are independently C.sub.1-3 alkyl, fluoro, bromo or chloro; and PA1 R.sup.6 is phenyl, benzyloxy, substituted phenyl or substituted benzyloxy in which the phenyl group in each case is substituted with one or more substituents selected from C.sub.1-3 alkyl, fluoro, bromo or chloro. PA1 A is C.sub.1-5 alkyl, Cl, F, OH, PA1 C.sub.1-5 alkyloxy, C.sub.2-6 alkanoylamiro, PA1 C.sub.1-5 alkyloxycarbonyl, phenyl, hydroxyalkyl, trifluromethyl-C.sub.2-8 alkanoylamino; PA1 E is a direct bond, --CH.sub.2 --, --CH.sub.2 CH.sub.2 --; PA1 R.sub.1, R.sub.2 and R.sub.3 are each selected from H, Cl or F, C.sub.1-4 alkyl, C.sub.1-4 chloroalkyl, C.sub.1-4 fluroalkyl, phenyl, phenyl substituted by chlorine or fluorine, C.sub.1-4 alkyoxy C.sub.2-8 alkanoyloxy, C.sub.2-8 alkanoyloxy-C.sub.1-5 alkyl, and PA1 OR.sub.4 in which R.sub.4 is H, C.sub.2-8 alkanoyl, benzoyl, phenyl, chlorophenyl or flurophenyl, phenyl C.sub.1-3 alkyl, C.sub.1-8 alkyl, C.sub.1-4 chloroalkyl or C.sub.1-4 flurcalkyl cycloalkyl-C.sub.1-3 alkyl, adamantyl-C.sub.1-3 alkyl, or substituted Phenyl-C.sub.1-3 alkyl, in which the substituents are selected from: chlorine or fluorine, C.sub.1-4 alkyoxy, C.sub.1-4 alkyl, or C.sub.1-4 chloroalkyl, C.sub.1-4 fluroalkyl; PA1 R.sup.5 is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and Pharmaceutically acceptable salts of the compounds (II) in which R.sub.5 is hydrogen. PA1 Z is phenyl or thiophenyl; or phenyl substituted with: phenyl, C.sub.1-5 alkyloxy, hydroxy, hydroxyalkyl, C.sub.1-5 alkyloxycarbonyl, C2-8- alkanoyloxy, or trifluromethyl-C.sub.2-8 alkanoylamino; PA1 E is --CH.sub.2 CH.sub.2 --; PA1 R.sub.1, R.sub.2 and R.sub.3 are each selected from H, Cl or F, PA1 Z is phenyl: or phenyl substituted with: phenyl, C.sub.1-5 alkyloxy, hydroxy, hydroxy-C.sub.1-5 alkyl, C.sub.1-5 alkyloxycarbonyl, or trifluromethyl-C.sub.2-8 -alkanoylamino; PA1 E is --CH.sub.2 CH.sub.2 --; PA1 R.sub.1 is hydrogen, PA1 R.sub.2 and R.sub.3 are each chloro in the 2 and 4 positions.
The totally synthetic antihypercholesterolemic compounds are disclosed in U.S. Pat. No. 4,375,475 and have the following general structural formulae: ##STR6## wherein R" is: ##STR7## wherein: E is --CH.sub.2 --, --CH.sub.2 CH.sub.2 -- or --CH=CH--;
Copending patent application Ser. No. 912,867 filed Sept. 29, 1986 discloses diaminoacyl derivatives of compactin, mevinolin and the totally synthetic HMG-CoA reductase inhibitors of structural formula: ##STR8## wherein R, R.sup.7, R.sup.98 and R.sup.10 and n are defined in the above cited application.
In relationship to the process of the instant invention, Cacchi and co-workers have carried out Michael type additions of aryl iodides to acyclic .alpha., .beta.-unsaturated aldehydes and ketones in the presence of a catalytic amount of Pd[II]and an excess of trialkylammonium formate. (3. Cacchi, F. LaTorre, G. Palmier; J. Orqanometallic Chem., 1984, 268, C48; S. Cacchi, G. Palmieri, Synthesis, 1984, 575.)